T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

Abraham L. Bayer, Sasha Smolgovsky, Njabulo Ngwenyama, Ana Hernández-Martínez, Kuljeet Kaur, Katherine Sulka, Junedh Amrute, Mark Aronovitz, Kory Lavine, Shruti Sharma, Pilar Alcaide

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

BACKGROUND: Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown. METHODS: We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88-/-mouse T cells at the transcript and protein level and performed several functional assays. RESULTS: Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88-/-T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling. CONCLUSIONS: Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.

Original languageEnglish
Pages (from-to)412-429
Number of pages18
JournalCirculation research
Volume133
Issue number5
DOIs
StatePublished - Aug 18 2023

Keywords

  • T lymphocytes
  • fibroblasts
  • fibrosis
  • heart failure
  • inflammation

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